Hemophilia A with inhibitor: Immune tolerance induction (ITI) in the mirror of time

Abstract

Inhibitor (neutralizing antibodies) development remains the most significant complication in patients with severe congenital hemophilia A receiving exogenous factor VIII (FVIII). Although our understanding of the pathophysiology of inhibitor development has advanced, the knowledge gained has not yet translated into a robust decline in incidence, with the overall risk remaining at ∼30%. Immune Tolerance Induction (ITI) is the only current method to successfully eradicate an inhibitor and achieve long-term tolerance. Although current practice utilizes a wide variety of ITI regimens, identification of an optimal regimen has not emerged. Over the last decade, the number of replacement products available in hemophilia has greatly expanded. The cumulative evidence with each product for use in ITI is often lacking. Most recently emicizumab, a humanized monoclonal bi-specific antibody that substitutes for the scaffolding effect of FVIIIa was approved; this agent prevents bleeding in both inhibitor and non-inhibitor patients. The use of emicizumab will bring about a new era in care that will require clinicians to challenge current practice paradigms including use and administration of ITI. This review will summarize the main clinical ITI data and practices for patients with severe congenital hemophilia A with inhibitors (CHAwI) over the last four decades and will highlight current studies in the field, with attention to open questions.

Keywords: Factor VIII; Hemophilia A; ITI; Immune tolerance induction; Inhibitors.